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EP2964022B1 - Combinaison de médicament antidouleur et ses utilisations - Google Patents

Combinaison de médicament antidouleur et ses utilisations Download PDF

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Publication number
EP2964022B1
EP2964022B1 EP14760959.8A EP14760959A EP2964022B1 EP 2964022 B1 EP2964022 B1 EP 2964022B1 EP 14760959 A EP14760959 A EP 14760959A EP 2964022 B1 EP2964022 B1 EP 2964022B1
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EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
dextromethorphan
opioid agonist
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EP14760959.8A
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German (de)
English (en)
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EP2964022A1 (fr
EP2964022A4 (fr
Inventor
Lawrence R. JAMES
Laura A. JAMES
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Mindlab LLC
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Mindlab LLC
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Publication of EP2964022A4 publication Critical patent/EP2964022A4/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Embodiments described herein relate to compositions and pharmaceutical compositions that can be used to treat or prevent pain or to produce analgesia.
  • Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limited, chronic pain, which can persist for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life. Pain is often treated opioid agonists, such as morphine, oxycodone and hydromorphone. Unfortunately, opioid agonists can have severe side effects that limit their use and effectiveness as treating and/or preventing pain. Therefore, the embodiments described herein provide for compositions that can be used to treat and/or prevent pain with significant and unexpected advantages over compositions currently used to treat or prevent pain.
  • Embodiments described herein provide pharmaceutical compositions comprising a NMDA antagonist; a CYP2D6 inhibitor; and an opioid agonist, in a ratio of 1:1:1 (wt:wt:wt).
  • the NMDA antagonist is chosen from one or more of dextromethorphan, a glycine antagonist, ifenprodil like compound, amantadine, MK-801 (dizocilpine; [5R,10S]-[+]-5-methyl-10,11-dihydro-5 H -dibenzo[ a , d ]cyclohepten-5,10-imine), ketamine, memantine, D-AP5 (D(-)-2-Amino-5-phosphonovaleric acid) , CPP (3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid), or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the CYP2D6 inhibitor is chosen from one or more of: quinidine, methadone, bupropion, cinacalcet, fluoxetine, paroxetine, duloxetine, sertraline, terbinafine, amiodarone, cimetidine, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the opioid agonist is chosen from one or more of the agonists described herein.
  • Embodiments described herein provide pharmaceutical compositions comprising dextromethorphan, or a pharmaceutically acceptable salt thereof; quinidine, or a pharmaceutically acceptable salt thereof; and an opioid agonist chosen from one or more of: morphine, oxycodone, and hydromorphone, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the compositions is formulated for simultaneous administration.
  • the composition comprises about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of the opioid agonist.
  • the composition comprises about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of the opioid agonist.
  • Embodiments described herein provide dosage forms comprising dextromethorphan, or a pharmaceutically acceptable salt thereof; quinidine, or a pharmaceutically acceptable salt thereof; and an opioid agonist chosen from one or more of: morphine, oxycodone, and hydromorphone, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the composition comprises about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg of the opioid agonist.
  • the method comprises administering to the subject a pharmaceutical composition described herein.
  • the pharmaceutical composition is administered every 4 hours, every 6 hours, every 8 hours, or every 12 hours.
  • the method does not comprise a risk evaluation mitigation strategy (REMS).
  • the subject is a subject in need of pain relief.
  • none of the components are administered for the purpose of avoiding withdrawal symptoms.
  • compositions are described herein. Each of the compositions described herein can also be pharmaceutical compositions.
  • compositions that unexpectedly and surprisingly treat or prevent pain with a lower amount of an opioid agonist and with fewer side effects while providing improved pain relief or analgesia.
  • the surprising results are from the combination of three compounds, an opioid agonist, a CYP2D6 inhibitor, and a NMDA antagonist.
  • the combination of the three types of compounds allow the compounds to stay as effective levels to produce improved pain relief or analgesia compared to the relief obtained with just one or two of the compounds.
  • the compositions treat or prevent pain relief better than with just the opioid agonist alone or the combination of the opioid agonist with the NMDA antagonist. Additionally, the compositions increase the bioavailability of the opioid agonist to the brain.
  • compositions also surprisingly and unexpectedly have an effect that is longer in duration than the opioid agonist alone.
  • the compositions also surprisingly and unexpectedly have a lower incidence of tolerance. That is, under certain circumstances increasing amounts of the opioid agonist are necessary to achieve the same level of pain relief.
  • the compositions can have a lower incidence of tolerance, thereby keeping the amount of the opioid agonist to a minimum, which reduces the adverse side effects that are common to the usage of opioid agonists.
  • opioid antagonist, NMDA antagonists, and CYP2D6 inhibitor administered or present in a composition as opposed to just two of an opioid agonist, dextromethorphan or quinidine.
  • the combination of an opioid agonist, NMDA antagonist, and CYP2D6 inhibitor has other reduced side effects compared to any of the components alone or in a combination of just two of them.
  • opioid side effects include, but are not limited to, weight loss, constipation, diarrhea, nausea, vomiting, stomach pain, loss of appetite, flushing ( e.g . warmth, redness, or tingly feeling), headache, dizziness, spinning sensation, memory problems, sleep problems (insomnia), or strange dreams. Therefore, the compositions described herein can reduce or lessen the side effects.
  • compositions that comprise an opioid agonist, a NMDA antagonists, and a CYP2D6 inhibitor.
  • the composition comprises an opioid agonist, dextromethorphan, quinidine, pharmaceutically acceptable salt of each or any of the foregoing, or any combination thereof is provided.
  • opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, me
  • the NMDA antagonist is chosen from one or more of dextromethorphan, a glycine antagonist, ifenprodil or ifenprodil like compounds, amantadine, MK-801 (dizocilpine; [5R,10S]-[+]-5-methyl-10,11-dihydro-5 H -dibenzo[ a , d ]cyclohepten-5,10-imine), ketamine, memantine, D-AP5 (D(-)-2-Amino-5-phosphonovaleric acid), CPP (3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid), or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • dextromethorphan a glycine antagonist
  • ifenprodil or ifenprodil like compounds amantadine
  • MK-801 dizocilpine; [5R,10S]-[+]-5-methyl-10,11-d
  • the NMDA antagonist is dextromethorphan.
  • glycine antagonist include, but are not limited to, GLYX-13, TK-40, 1-Aminocyclopropanecarboxylic acid (ACPC), 7-Chlorokynurenic acid, DCKA (5,7-dichlorokynurenic acid), kynurenic acid, lacosamide, L-phenylalanine, and the like.
  • ACPC 1-Aminocyclopropanecarboxylic acid
  • DCKA 5,7-dichlorokynurenic acid
  • kynurenic acid lacosamide
  • L-phenylalanine and the like.
  • the compositions and dosage forms described herein can have one or more of the glycine antagonists.
  • the dextromethorphan is a hydrate, such as but not limited to, dextromethorphan hydrobromide monohydrate.
  • the CYP2D6 inhibitor chosen from one or more of: quinidine, methadone, bupropion, cinacalcet, fluoxetine, paroxetine, duloxetine, sertraline, terbinafine, amiodarone, cimetidine, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the CYP2D6 inhibitor is quinidine.
  • the composition is formulated for simultaneous administration.
  • simultaneous administration means that each of the active ingredients or therapeutic agents are administered substantially or exactly at the same time.
  • the agents may be absorbed or become bioavailable at different rates or times, but the administration of the components, ingredients, or agents, is simultaneous.
  • the administration is not simultaneous.
  • Simultaneous administration can be achieved by having each of the components (e.g ., opioid agonist, NDMA antagonist, and CYP2D6 inhibitor) in the same dosage form.
  • Simultaneous administration can also be achieved where each of the components are not in the same dosage form, but are administered substantially or exactly at the same time.
  • the composition comprises about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg of the opioid agonist. In some embodiments, the composition comprises from about 10 to about 100 mg, from about 10 to about 90 mg, from about 10 to about 80 mg, from about 10 to about 70 mg, from about 10 to about 60 mg, from about 10 to about 50 mg, from about 10 to about 40 mg, from about 10 to about 30 mg, from about 10 to about 20 mg, from about 20 to about 100 mg, from about 20 to about 90 mg, from about 20 to about 80 mg, from about 20 to about 70 mg, from about 20 to about 60 mg, from about 20 to about 50 mg, from about 20 to about 40 mg, from about 20 to about 30 mg, from about 30 to about 100 mg, from about 30 to about 90 mg, from about 30 to about 80 mg, from about 30 to about 70 mg, from about 30 to about 60 mg, from about 30 to about 50 mg, from about 30 to about 40 mg, from about 40 to about 100 mg, from about 40 to about 90 mg, from about
  • the composition comprises an opioid antagonist.
  • the oral dosage form can comprise an opioid antagonist.
  • the oral dosage form comprises a sequestered opioid antagonist.
  • a sequestered opioid antagonist is one that is not bioavailable unless the oral dosage form is tampered with or adulterated. Opioids can be abused for their euphoric effect and if the dosage form is a controlled release or sustained release dosage form, crushing the dosage form can increase the bioavailability of the opioid agonist. Therefore, to prevent abuse, the dosage form can be made with the opioid antagonist such that the activity of opioid agonist is inhibited if the dosage form is altered, adulterated or tampered with by the subject using the dosage form.
  • the oral dosage form further comprises a sequestered opioid antagonist which is not released when the dosage form is administered intact.
  • the sequestered opioid antagonist is in an amount which will negate the euphoric effect of the opioid agonist when the dosage form is tampered with and misused by a human.
  • the form can be misused by administering the tampered dosage form orally, parenterally, intranasally or sublingually.
  • the sequestered antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazocine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.
  • Other examples of sequestered antagonists and formulations thereof are described in U.S. Patent 8,231,901 .
  • compositions, dosage forms, and such described herein can be used to produce analgesia.
  • the composition or pharmaceutical composition or dosage form is administered every 4 hours, every 6 hours, every 8 hours, or every 12 hours.
  • a REMS can include a medication guide, patient package insert, a communication plan, elements to assure safe use, an implementation system, or any combination thereof. Because the compositions described herein may use less amounts of the opioid agonist, risk evaluation mitigation strategies may not need to be used. Therefore, in some embodiments, the method does not comprise the use of a risk evaluation mitigation strategy or any element of a REMS, some of which are described herein.
  • the composition can comprise non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfen
  • non-steroidal anti-inflammatory agents such aspir
  • analgesic, antipyretic, nonsteroidal antiinflammatory drugs include salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para aminophennol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid, and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxy
  • Cox II inhibitors include, but are not limited to, rofecoxib and celecoxib.
  • compositions described herein can also comprise antimigraine agents, which include but are not limited to, alpiropride, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate, fonazine, lisuride, lomerizine, methysergide oxetorone, pizotyline, and mixtures thereof.
  • antimigraine agents include but are not limited to, alpiropride, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate, fonazine, lisuride, lomerizine, methysergide oxetorone, pizotyline, and mixtures thereof.
  • the pain treated, ameliorated, or prevented in accordance with the methods described herein can be acute pain or chronic pain, such as, but not limited to, nociceptive pain, neuropathic pain and psychogenic pain, and can be cancer related or not associated with cancer.
  • Example of "nociceptive pain” include, but are not limited to, pain caused by injury to body tissues, including, without limitation, by a cut, bruise, bone fracture, crush injury, burn, surgery, and the like.
  • the pain is somatic pain.
  • the term "somatic pain” is used to refer to pain arising from bone, joint, muscle, skin, or connective tissue. This type of pain is typically aching or throbbing in quality and is well localized.
  • neurode pain is used herein to refer to pain originating from abnormal processing of sensory input by the peripheral or central nervous system.
  • the pain can also be as a result of surgery, which can be referred to as post-surgical pain. Examples of surgery include, but are not limited to, dental or trauma, orthopedic surgery, and the like.
  • the compositions described herein can be used, in some embodiments, to treat or prevent these types of pain as well as others.
  • compositions described herein can also be administered in a therapeutically effective amount to treat, ameliorate, or prevent pain.
  • the compositions described herein can also be administered in a therapeutically effective amount to produce analgesia.
  • the compositions described herein are administered to produce effective analgesia within 1 hour of administration.
  • the compositions described herein are administered to produce enhanced analgesia as compared to the opioid agonist given alone or in combination with NMDA antagonist, but without a CYP2D6 inhibitor.
  • the NMDA antagonist is one described herein, including, but not limited to dextromethorphan.
  • the CYP2D6 inhibitor is one described herein, including, but not limited to, quinidine.
  • the analgesia or pain relief is increased by at least 2-3 times when the opioid agonist is administered in combination with CYP2D6 inhibitor and NMDA antagonist as compared to just the opioid agonist alone or as compared to the opioid agonist in combination with NMDA antagonist.
  • none of the components (i . e . opioid agonist, NMDA antagonist, or CYP2D6 inhibitor) of a pharmaceutical composition are administered to the subject to avoid withdrawal symptoms.
  • Opioids and/or other pain medications can be addictive. Thus, as medications are changed the subject may be weaned off of a medication to avoid withdrawal symptoms.
  • the different components are administered to treat, ameliorate, or prevent pain or to produce analgesia and not for the purpose of avoiding and/or treating withdrawal symptoms. That is, in some embodiments, the compositions, or dosage forms are administered with the intent treat or alleviate the symptoms of pain or to produce analgesia and not for the intent to avoid or treat withdrawal symptoms that can be associated with addiction.
  • the pharmaceutical compositions can be administered in a dosage form.
  • the dosage form comprises an opioid agonist, a NMDA antagonist and a CYP2D6 inhibitor.
  • the dosage form comprises each of the components in the ratios described herein.
  • the dosage form is a pill, capsule, tablet, fast dissolving tablet ( e.g . reditab and the like), liquid, film, fast dissolving film, which can also be referred to as oral wafers or oral films. Examples of these are described in Int J Pharm Investig. 2013 Apr-Jun; 3(2): 67-76 , Curr Drug Deliv. 2013 Dec;10(6):667-84 , Curr Drug Deliv.
  • the compositions described herein are a dosage form.
  • a dosage form is where each of the active ingredients or components are mixed together prior to administration. Examples of dosage forms are described herein and include, but are not limited to, pills, capsule, liquid, tablet, and the like.
  • the dosage form can have the same components as discussed herein for the compositions. The ratios of the components can also be the same.
  • the dosage form is suitable for oral administration, topical administration, or parenteral administration.
  • the compositions or dosage forms can also be administered sublingually, bucally, intranasal, and the like.
  • the compositions described herein can be administered by any suitable method.
  • the composition is swallowed. In some embodiments, the composition is not swallowed.
  • the composition may also be, for example, administered subcutaneously, intramuscularly, intravenously, transdermally or vaginally.
  • the combination of the opioid agonist, NMDA antagonist, and CYP2D6 inhibitor is administered simultaneously, separately, or a combination thereof. Therefore, in some embodiments, CYP2D6 inhibitor is administered before the opioid agonist or NMDA antagonist.
  • the CYP2D6 inhibitor is administered with the opioid agonist and then followed by the administration of NMDA antagonist.
  • CYP2D6 inhibitor is administered with NMDA antagonist and then followed by the administration of the opioid agonist.
  • each component is administered sequentially in any order. In some embodiments, they are administered concurrently in the same dosage form or in separate dosage forms.
  • the compositions can be administered to a subject, animal, patient, or mammal in need thereof.
  • the phrase "in need thereof' means that the animal, subject, patient or mammal has been identified as having a need for the particular method, use, or treatment. In some embodiments, the identification can be by any means of diagnosis.
  • the animal or mammal can be in need thereof.
  • the animal or mammal is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent.
  • the need, or intent is to treat, ameliorate, or prevent pain, or produce analgesia.
  • the term "mammal” means a rodent (i.e., a mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or a human.
  • the mammal is a human.
  • the mammal is a non-human mammal.
  • the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • the phrase "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • composition or “pharmaceutical composition” it is further meant that the carrier, solvent, excipients and salt must be compatible with the active ingredient of the formulation (e.g. a compound described herein). It is understood by those of ordinary skill in this art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally interchangeable, and they are so used for the purposes of this application. As discussed herein, the composition described herein can be a pharmaceutical composition. The composition can also have a pharmaceutically acceptable salt of the parent compound.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • salts can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, and the like. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990 ).
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • treating includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
  • Treating or “treatment” of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
  • the treatment of pain would be the reduction in the pain sensation that one would have in the absence of the composition being administered.
  • the terms "treatment of' and “treating” pain include the lessening of the severity of or cessation of pain. In some embodiments, it refers to decreasing the overall frequency of episodes of pain.
  • preventing means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state. Preventing pain may also refer to a subject not having as great of a pain sensation as the subject would have had had the composition not been administered.
  • the phrase "therapeutically effective amount” means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the therapeutic effect is dependent upon the disorder being treated or the biological effect desired.
  • the therapeutic effect can be a decrease in the severity of symptoms associated with the disorder and/or inhibition (partial or complete) of progression of the disorder, or improved treatment, healing, prevention or elimination of a disorder, or side-effects.
  • the amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the subject. Optimal amounts can also be determined based on monitoring of the subject's response to treatment.
  • the compositions can also be administered in a therapeutically effective amount.
  • compositions which includes dosage forms, can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the animal.
  • a pharmaceutically acceptable excipient can be, but not limited to, liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to an animal.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
  • suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions described herein can, for example, take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the composition is in the form of a capsule (see e.g., U.S. Pat. No. 5,698,155 ).
  • suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995 ).
  • compositions described herein can also be formulated to be a controlled- or sustained-release pharmaceutical compositions.
  • Advantages of controlled- or sustained-release compositions include extended activity of the drug or combination of drugs, reduced dosage frequency, and increased patient compliance.
  • controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the compounds, and can thus reduce the occurrence of adverse side effects.
  • controlled- or sustained-release compositions can initially release an amount of the composition or component that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the composition or component to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the composition or the individual components can be released from the dosage form at a rate that will replace the amount of composition or individual components being metabolized and excreted from the body.
  • Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions described herein also consist essentially of, or consist of, the recited components, and that the processes described herein also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the process remains operable. Moreover, two or more steps or actions can be conducted simultaneously. Compositions can also refers to the dosage forms.
  • a composition includes a plurality of such compositions, as well as a single composition
  • a reference to “a therapeutic agent” is a reference to one or more therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled in the art, and so forth.
  • a reference to “a host cell” includes a plurality of such host cells
  • a reference to “an antibody” is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.
  • Example 1 Administration of Quinidine/Morphine/Dextromethorphan treats pain.
  • quinidine The ability of quinidine (Q) to enhance the analgesic effects of MS:DM and reduce tolerance and dependence of MS and MS:DM in rats is determined.
  • Adult Sprague-Dawly rats are used. All experimental protocols are done at a licensed research facility having an institutional animal care and use committee (IACUC) that conforms to the national institute of health (NIH) office of laboratory animal welfare (OLAW).
  • IACUC institutional animal care and use committee
  • Morphine sulfate pentahydrate (MS), Dextromethorphan hydrobromide monohydrate (DM), quinidine (Q), and/or Naloxone hydrochloride are ordered from commercially available suppliers and manufacturers. Each component is administered orally through a rodent feeding tube. Rats exhibiting signs of misfeeding (choking, irritation, and irregular breathing) are assessed following each dose and treated appropriately.
  • the baseline tail-flick latencies of the rats are be set at 3.5 to 4.5 seconds. To minimize tissue damage, and if no tail-flick occurs after 8 seconds, the light (e.g. heat) source is automatically turned off. The average of three tail-flick trials separated by a 1 min inter trial interval is used to determine the mean baseline latency (BL).
  • the analgesic effects of MS, MS:DM, and MS:DM:Q and the development of tolerance is determined by measuring test (tail-flick) latencies (TL) after drug administration.
  • Tolerance to MS in rats is determined using the tail flick pain model, and is measured as the time difference between baseline tail flick latencies and test tail flick latencies after MS, MS:DM, and MS:DM:Q administration. Results of the test are that the tricombination of MS:DM:Q have a statistically significant increase in the tail flick latencies compared to baseline and as compared to MS and MS:DM and no drug administration. Additionally, dependence is determined by observing the three physical characteristics of escape jumping, teeth chattering, and wet-dog shakes for 10-15 minutes duration, following intraperitoneal Naloxone challenge.
  • the dose dependent analgesic effects of MS in rats is determined using an oral administration of a range of MS doses, using the tail flick pain model described above.
  • Tail flick latencies are measured at 1, 2, and 3 hours after oral treatment of MS to determine maximal analgesic effects of MS and ED 50 .
  • the oral MS administration is repeated until tolerance and dependence are achieved. This is done by twice daily dosing of MS at the ED 50 dose (approximately 30 mg/kg) for 5, 10, and 15 days. Tail flick latencies are measured 90 minutes after each treatment until day 15.
  • Naloxone is given IP on days 5, 10, and 15 to one group of rats and signs of withdrawal are observed for 10 minutes after injection.
  • One saline treated group of rats will be used as control for all time points.
  • Escape jumping, teeth chattering, and wet-dog shaking are used to assess physical dependence on MS compared to MS:DM, or MS:DM:Q. These observations are determined following naloxone challenge (10 mg/kg, subcutaneously). The frequency of attempted escape jumping from containers housing the individual rats, and the frequency of episodes of teeth chattering, or wet-dog shaking are counted for a duration of 10 min after naloxone challenge.
  • a therapeutically effective ratio range of combined administration of MS, DM, and Q that prevents or reduces the development of morphine tolerance and dependence.
  • Three doses of MS ED90, ED50, and ED30 doses, respectively) are used to determine whether MS / DM / Q ratios are similar in preventing the development of morphine tolerance and dependence induced by different dose levels of MS.
  • baseline tail-flick latencies of each rat is obtained before dosing.
  • Each group of rats receives oral administration of one of the drug combinations or saline twice a day for 30 days.
  • the analgesic effects of MS is examined at 90 min after the oral feeding using the tail-flick test on day, 5, 10, 15 or 30 of the treatment schedule. The choice of this 30-day treatment regimen is dependent on results of the time course experiment.
  • 10 mg/kg naloxone is given intraperitoneally to each rat, and withdrawal signs are observed and recorded for 10 min following injection.
  • the time course of the DM-mediated increase in the acute analgesic effects of MS and compare it to MS:DM:Q is determined.
  • MS ED30 dose is used in order to avoid maximal analgesic effects of a high MS dose alone.
  • Four groups ( n 12/group) of rats each receive a single oral administration of MS alone, a combination of MS and DM, DM alone, or MS:DM:Q (based upon the optimal combination ratio of MS:DM to Q determined above).
  • the tail-flick test is recorded before and every 30 min after drug administration until tail-flick latencies are back to the baseline level.
  • Example 2 The Combination of Morphine, Dextromethorphan, and Quinidine Potentiates Pain Relief as Compared to Morphine alone or Morphine in Combination with Dextromethorphan.
  • the preparations tested in the rats were as follows: 1) vehicle (control), 2) morphine (dose of 25 mg/kg); 3) dextromethorphan (dose of 25 mg/kg); 4) morphine/dextromethorphan at a 1:1 ratio (wt:wt); 5) morphine/dextromethorphan/quinidine at a ratio of 1:1:0.1; 6) morphine/dextromethorphan/ quinidine at a ratio of 1:1:0.5; and 7) morphine/dextromethorphan/quinidine at a ratio of 1:1:1.
  • results shown below indicate that the combination of morphine/dextromethorphan/quinidine at a ratio of 1:1:1 significantly enhanced the analgesic effects of morphine alone and the combination of morphine and dextromethorphan. Additionally, the tri-combination of morphine/dextromethorphan/quinidine at a ratio of 1:1:1 lead to the increased analgesia within 1 hour of administration as compared to morphine alone or the combination of morphine and dextromethorphan. At 1 hour the tri-combination had a mean of 17.90 seconds, whereas the combination of morphine and dextromethorphan had a mean of 6.84.
  • the combination had 2.6 times more analgesia than the combination of morphine and dextromethorphan without quinidine.
  • the tri-combination was also more effective at providing analgesia as compared to morphine alone.
  • the mean of all seven animals shows an almost two fold increase in analgesia, however, when one animal is removed, which appears to have been an outlier, the tri-combination increases analgesia by about 2.7 times.
  • morphine alone showed a time of 6.5
  • the combination of morphine and dextromethorphan showed a time of 5.60
  • the tri-combination of morphine/dextromethorphan/quinidine at a ratio of 1:1:1 showed a time of 16.10, which shows that the tri-combination increases analgesia by about 2.5 times versus morphine alone and 2.875 times more analgesia when compared to the combination of morphine and dextromethorphan without quinidine.
  • the increase in analgesia caused by the tri-combination was observed through at least 8 hours after administration.

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Claims (10)

  1. Composition pharmaceutique comprenant :
    un antagoniste de NMDA ;
    un inhibiteur de CYP2D6 ; et
    un agoniste d'opioïde,
    dans laquelle le rapport de l'agoniste d'opioïde à l'antagoniste de NMDA à l'inhibiteur de CYP2D6 est d'environ 1:1:1 (m:m:m).
  2. Composition pharmaceutique selon la revendication 1, dans laquelle l'agoniste d'opioïde est choisi parmi l'un ou plusieurs parmi : la morphine, l'oxycodone et l'hydromorphone, ou un sel pharmaceutiquement acceptable de celles-ci, ou une combinaison quelconque de celles-ci.
  3. Composition pharmaceutique selon les revendications 1 ou 2, dans laquelle l'antagoniste de NMDA est choisi parmi l'un ou plusieurs parmi le dextrométhorphane, un antagoniste de glycine, un composé de type ifenprodil, l'amantadine, MK-801 (dizocilpine ; [5R,10S]-[+]-5-méthyl-10,11-dihydro-5/7-dibenzo[a,d]cycloheptén-5,10-imine), kétamine, mémantine, D-AP5 (acide D(-)-2-amino-5-phosphonovalérique) et CPP (acide 3-(2-carboxypipérazin-4-yl)propyl-1-phosphonique), ou un sel pharmaceutiquement acceptable de ceux-ci, ou une combinaison quelconque de ceux-ci.
  4. Composition pharmaceutique selon l'une quelconque des revendications 1 à 3, dans laquelle l'antagoniste de NMDA est le dextrométhorphane, ou un sel pharmaceutiquement acceptable de ceux-ci, tel que le bromhydrate de dextrométhorphane monohydraté.
  5. Composition pharmaceutique selon l'une quelconque des revendications 1 à 4, dans laquelle l'inhibiteur de CYP2D6 est choisi parmi l'un ou plusieurs parmi : la quinidine, le bupropion, le cinacalcet, la fluoxétine, la paroxétine, la duloxétine, la sertraline, la terbinafine, l'amiodarone et la cimétidine, ou un sel pharmaceutiquement acceptable de ceux-ci, ou une combinaison quelconque de ceux-ci.
  6. Composition pharmaceutique selon l'une quelconque des revendications 1 à 5, dans laquelle l'inhibiteur de CYP2D6 est la quinidine, ou un sel pharmaceutiquement acceptable de celle-ci, tel que le gluconate de quinidine ou le sulfate de quinidine.
  7. Composition pharmaceutique selon l'une quelconque des revendications 1 à 6, la composition pharmaceutique étant formulée pour administration simultanée.
  8. Composition pharmaceutique selon la revendication 1, la composition comprenant un agoniste d'opioïde, du dextrométhorphane, ou un sel pharmaceutiquement acceptable de celui-ci, et de la quinidine, ou un sel pharmaceutiquement acceptable de celle-ci, dans laquelle le rapport de l'agoniste d'opioïde, ou un sel pharmaceutiquement acceptable de celui-ci, au dextrométhorphane, ou un sel pharmaceutiquement acceptable de celui-ci, à la quinidine, ou un sel pharmaceutiquement acceptable de celle-ci est d'environ 1:1:1 (m:m:m),
    dans laquelle l'agoniste d'opioïde est la morphine, l'oxycodone ou l'hydromorphone, ou un sel pharmaceutiquement acceptable de celles-ci.
  9. Composition pharmaceutique selon l'une quelconque des revendications 1 à 8, la composition pharmaceutique étant une forme pharmaceutique choisie dans le groupe constitué d'une forme pharmaceutique orale ou d'un film à dissolution rapide.
  10. Composition pharmaceutique selon l'une quelconque des revendications 1 à 9 pour utilisation dans un procédé de traitement ou de prévention de la douleur ou pour produire une analgésie chez un sujet.
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US20160030417A1 (en) 2016-02-04
EP2964022A1 (fr) 2016-01-13
AU2017272152A1 (en) 2017-12-21
CN105491885B (zh) 2018-09-25
US20190111049A1 (en) 2019-04-18
US10716784B2 (en) 2020-07-21
CA2903757A1 (fr) 2014-09-12
EP2964022A4 (fr) 2016-12-14
US20200316056A1 (en) 2020-10-08
JP6495191B2 (ja) 2019-04-03
HK1223246A1 (zh) 2017-07-28
AU2014225422A1 (en) 2015-10-15
JP2016510762A (ja) 2016-04-11
US20230372326A1 (en) 2023-11-23
AU2017272152B2 (en) 2019-11-21
US20140256763A1 (en) 2014-09-11
CN105491885A (zh) 2016-04-13
HK1217408A1 (en) 2017-01-13
WO2014138669A1 (fr) 2014-09-12

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